formulation and in-vitro evaluation of serotonin- …

www.wjpps.com Vol 6, Issue 12, 2017.

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Shashidhar et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND IN-VITRO EVALUATION OF SEROTONIN-

5HT-1b and SEROTONIN-5HT-1d RECEPTOR AGONIST AGENT-

ZOLMITRIPTAN-AN ANTI-MIGRAINE DRUG

Dr. Shashidhar P.*, Dr. D. Ramakrishna, Dr. M. Sunitha and Syeda Humera

Shadan Womens College of Pharmacy, Kahirtabad, Hyderabad, Telangana.

ABSTRACT

Oral drug delivery systems occupy most common route of dosage form

administration, of which oral disintegrating tablets plays key

significant role in case of minimum time required to get effective

therapeutic concentration of a given active pharmaceutical ingredient

as ORDs tablets. The selected Zolmitriptan was prepared into oral

disintegrating tablets using PRECROL, ACE SULFATE AND

CROSSPOVIDONE as major inactive ingredients. FTIR spectra revels

that, there is no significant interaction between the pure drug

Zolmitriptan and other inactive ingredients used. Total 10 formulation

trials were prepared of which trial T-10 was optimized based on the characteristic properties

and in-vitro evaluation parameters. Physical evaluation of blends and tablets of all the trials

gave optimum range results of angle of repose 23.3 to 28.8, weight variation 97-101,

hardness 2.3 to 2.6Kg/Cm2 and friability was found to be 0.3 to 0.9 percent for all 10 trials.

Melt granulation and direct compression techniques were implemented in present work to

prepare ORDs tablets, among which trial T-10 tablets prepared by direction compression

method were optimized. The % drug release was fitted to various kinetic models to see the

release rate of drug form prepared in-house ORDs tablets, and release rate was observed to be

KORESMEYER PEPPAS-0.989>FIRST ORDER-0.975>HIGUCHIS PLOT-0.926. The

prepared ORDs tablets give immediate therapeutic activity in minimizing migraine.

KEYWORDS: ORDs, oral disintegrating tablets, Zolmitriptan.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 6, Issue 12, 755-779 Research Article ISSN 2278 – 4357

Article Received on

27 Sept. 2017,

Revised on 16 October 2017,

Accepted on 05 Nov. 2017

DOI: 10.20959/wjpps201712-10543

*Corresponding Author

Dr. Shashidhar P.

Shadan Womens College of

Pharmacy, Kahirtabad,

Hyderabad, Telangana.


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INTRODUCTION

Tablets dosage forms which unexpectedly disintegrate inside the mouth and may be taken

without water have emerge as extraordinarily famous in current years. Those products offer

the convenience of a tablet with the ease of swallowing a liquid. These dosages are of

specific benefit in certain patient‟s in along with kids, elderly, and psychiatric sufferers.

Clinical situations which include pain, migraine, nausea, panic attack, allergic conditions,

cough or bloodless, and Alzheimer‟s may benefit from these dosage paperwork. In spite of

awesome innovations in drug shipping, the oral course stays the preferred path for

administration of therapeutic retailers due to correct dosage, low price therapy, self remedy,

non invasive technique and ease of management leading to excessive degree of affected

person compliance.[1]

Significance of ODTS[2]

ODTs provide dual advantages of stable dosage bureaucracy and liquid dosage paperwork in

conjunction with special capabilities which encompass.

- Correct dosing: Being unit stable dosage paperwork, offer luxury of accurate dosing,

clean portability and production, excellent bodily and chemical stability and an ideal

opportunity for pediatric and geriatric patients.

- More suitable bioavailability: Bioavailability of drugs is greater due to absorption from

mouth, pharynx and esophagus.

Advantages of ODTS[3]

e• Ease of administration to patients who cannot swallow, which include the aged, stroke

sufferers and bedridden sufferers; sufferers who ought to not swallow, inclusive of renal

failure sufferers; and who refuse to swallow, along with pediatrics, geriatric and psychiatric

patients.

• affected person‟s compliance for disabled bedridden sufferers and for travelling and busy

folks that do no longer have ready access to water.

• excellent mouth sense assets of ODTS enables to alternate the fundamental view of

medication as "bitter tablet", in particular for pediatric patients due to advanced taste of bitter

pills.

• comfort of management and correct dosing in comparison to liquid formulations.

• Advantage of liquid remedy inside the form of solid practice.


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• More fast drug absorption from the pre-gastric location i.e. mouth, pharynx and oesophagus

which may produce rapid onset of motion.

• Pregastric absorption can bring about stepped forward bioavailability, reduced dose and

improved medical performance by means of lowering side effects.

• New enterprise possibilities: product differentiation, line extension and lifestyles-cycle

control, exclusivity of product promotion and patent-existence extension.

Best of ODTs[3]

They should

• Not require water to swallow and ought to dissolve or crumble within the mouth inside

some seconds.

• Allow high drug loading.

• Be well matched with flavor masking and other excipients.

• Have a pleasant mouth experience.

• Depart minimum or no residue in the mouth after oral administration.

• Have sufficient electricity to face up to the rigors of the manufacturing method and submit

production managing.

• Show off low sensitivity to environmental conditions including humidity and temperature.

• Be adaptable and amenable to current processing and packaging equipment.

• Allow the manufacture of drugs using conventional processing and packaging equipments at

low price.

ODTs as a strong dosage form containing medicinal materials which disintegrates swiftly,

usually inside a depend of seconds, when placed under the mouth, ODTs are acknowledged

by various names inclusive of “rapid-melting, fast-dissolving, mouth melts, mouth dissolving,

brief disintegrating, porous tablets, rapimelts or orodispersible tablets.”

SUPERDISINTEGRANTS[4]

Disintegrants are substances automatically covered in tablet formulations and in a few tough

shell pill formulations to promote moisture penetration and dispersion of the matrix of dosage

form in dissolution fluids. An oral solid dosage shape must preferably disperse into the

number one particles from which it was organized. Remarkable disintegrants are typically

used at a low awareness, generally 1-10% by way of weight relative to general weight of

dosage unit. Typically applicable disintegrants are Cross Carmellose Sodium (Ac-Di-Sol),

Crosspovidone (Cp), and Sodium starch glycolate (SSG) and so on. Which constitute instance


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of cross linked cellulose, cross linked polymer and cross linked starch respectively. Selection

of appropriate system excipients and manufacturing generation is important for obtaining the

optimized layout capabilities of orally disintegrating dosage bureaucracy. Ideally, super

disintegrates should cause the pill to disrupt, now not only into the granules from which it

turned into compressed however also into powder particles from which the granules had been

prepared.

Choice of Super disintegrants

Even though super disintegrants more often than not affect the charge of disintegration,

however when used at high degrees they can also affect mouth feel, tablet hardness and

friability. For this reason, numerous perfect elements to be taken into consideration whilst

deciding on the right super disintegrants for a particular formulation have to: produce speedy

disintegration, whilst pill comes in contact with saliva in the mouth/oral cavity. Be

compactable enough to provide much less friable drugs. Produce excellent mouth experience

to the patients. As a result, small particle length is favored to reap patient compliance. Have

right with the flow, because it improves the float characteristics of total blend.

Mechanism of Movement of Disintegrants

Numerous mechanisms proposed on this challenge encompass water wicking, swelling,

deformation restoration, repulsion and heat of wetting. it appears in all likelihood that no

single mechanism can give an explanation for the complex conduct of the disintegrants.

However, each of those proposed mechanisms offers some understanding of different aspects

of disintegrant movement.

Water Wicking[5]

The capacity of disintegrant to draw water into the porous network of tablet is critical for

effective disintegration. on preserving the pill into suitable aqueous medium, the medium

enters into tablet and replaces the air adsorbed on the debris which weakens the

intermolecular bonds and breaks the pill into exceptional debris. Water uptake through tablet

relies upon hydrophilicity of the drug/excipients and on tableting situations. In contrast to

swelling, which is mainly a measure of quantity expansion with accompanying force

generation, water wicking isn't necessarily accompanied by a quantity growth. The potential

of a system to draw water may be summarized by using Washburn‟s Equation.

L2 = (Γ Cosθ/2η) × Rt


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The Washburn equation is just too simplistic to use to a dynamic tablet-disintegration

manner, however it does display that any trade in the surface anxiety (γ), pore length (r),

strong-liquid touch perspective (θ) or liquid viscosity (η) could change the water wicking

performance. l is the period of water penetration inside the capillary and t is the time. This

technique is also considered as capillary action approach.

Swelling

Even though water penetration is a essential first step for disintegration, swelling might be

the maximum broadly typical mechanism of movement for tablet disintegrants. For swelling

to be effective as a mechanism of disintegration, there ought to be a superstructure against

which disintegrant swells.

Discern represents the disintegration of pill by wicking and swelling. Swelling of the

disintegrant in opposition to the matrix ends in development of a swelling pressure. A big

inner porosity within the dosage form wherein a whole lot of the swelling may be

accommodated reduces the effectiveness of the disintegrant. Then again, sufficient swelling

force is exerted inside the pill with low porosity. It's far worthwhile to note that if packing

fraction may be very high, fluid is not able to penetrate in the pill and disintegration is once

more slowed down.

Warmth of Wetting[6]

When disintegrants with exothermic houses get wetted, localized stress is created because of

capillary air expansion, which aids in disintegration of pill. This rationalization, however, is

confined to only some sorts of disintegrants and cannot describe the action of most cutting-

edge disintegrating agents.

Wicking: Disintegrant draws water into the Particles swell and break up the pores and

reduces the physical matrix.

Swelling: swelling sets up; Bonding forces between particles. Localized stress spreads

through-out the matrix.

Disintegration of table via wicking and swelling Due to Release of gases Carbon dioxide gets

released inside capsules on wetting because of interplay among bicarbonate and carbonate

with citric acid or tartaric acid. The pill disintegrates due to era of stress inside the tablet.

This bubbling mixture is use very rapidly dissolving drugs or speedy disintegrating pill. As


760


those disintegrants are fairly touchy to small modifications in humidity stage and

temperature, strict manage of environment is required throughout guidance of the capsules.

The bubbling combo is both introduced immediately prior to compression or can be brought

into separate fractions of formulation.

Particle repulsive forces[7]

That is every other mechanism of disintegration that attempts to provide an explanation for

the swelling of pill made with non-swellable disintegrants. Guyot-Hermann proposed a

particle-particle repulsion idea to give an explanation for the remark that debris which do

now not swell drastically along with starch, ought to nonetheless disintegrants tablets. In step

with this idea, water penetrates into tablet thru hydrophilic pores and a non-stop starch

network is created that could convey water from one particle to the following, providing a

enormous hydrostatic stress. The water then penetrates between starch grains due to its

affinity for starch surfaces, thereby breaking hydrogen bonds and different forces keeping the

pill collectively. The electric repulsive forces among particles are the mechanism of

disintegration and water is needed for it.

Deformation healing

Deformation restoration principle implies that the form of disintegrant debris is distorted

during compression and the debris return to their precompression shape upon wetting,

thereby causing the tablet to break apart. This kind of phenomenon can be an crucial factor of

the mechanism of motion of disintegrants inclusive of crospovidone and starch that showcase

little or no swelling. Disintegration of pill by using deformation in addition to repulsion is

illustrated in figure

Deformation Repulsion

Figure no 01: process of disintegration of tablets.


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Particles swell to pre-compression

Water is drawn into the pores and size and break up the matrix particles repel each other due

to the resulting electrical force.

Disintegration by deformation and repulsion by enzymatic response.

Enzymes present inside the body also act as disintegrants. Those enzymes dearth the binding

movement of binder and allows in disintegration. Due to swelling, pressure is exerted within

the outer route that reasons the tablet to burst or the improved absorption of water ends in

significant boom inside the quantity of granules to sell disintegration.

Selection of drug applicants for ODTs[8]

Numerous factors should be considered at the same time as deciding on the suitable drug

candidate for improvement of orally disintegrating dosage forms. The last traits of a drug for

dissolution within the mouth and pregastric absorption from ODTs include.

- Loose from sour flavor.

- Dose decrease than 20 mg.

- Small to mild molecular weight.

- Precise solubility in water and saliva.

- Partly un-ionized on the oral cavity's pH.

- Capacity to diffuse and partition into the epithelium of the top GIT (log P >1, or ideally

>2).

- Capacity to permeate oral mucosal tissue. In evaluation, the following traits can also

render a drug incorrect for delivery as an orally disintegrating dosage shape:

- Short 1/2-existence and common dosing.

- Very bitter or in any other case unacceptable taste because flavor overlaying cannot be

efficiently executed.


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Table no 01: Description of disintegrants used in pharmaceutical industries.

[9]

Popular Disintegrants used

in tablets Mechanism

Starch

Disintegrate forms pathways throughout the tablet matrix

that enable water to draw into the structure by capillary

action thus leading to disruption of tablet.

Pregelatinized starch Responsible for increased dissolution rate from this tablet

is rapid disintegration due to superior swelling capacity.

Sodium Starch Glycolate

Involves rapid absorption of water leading to an enormous

increase in volume of granules result in rapid and uniform

disintegration.

Cross-linked polyvinyl

Pyrrolidone

The capillary activity of cross povidone for water is

responsible for its tablet disintegration property.

Cellulose They show their ability to swell on contact with water

results in rapid tablet disintegration.

Microcrystalline Cellulose

Allowing water to enter the tablet matrix by means of

capillary pores, which break the hydrogen bonding

between adjacent bundles of cellulose microcrystals and

exhibit very good disintegrant property

Alginates High affinity for water absorption and high sorption

capacity make it an excellent disintegrant.

International Journal of

Pharmaceutical Sciences and

Research ISSN: 0975-8232

Available online on

www.ijpsr.com 24 Soy

polysaccharides

Natural super disintegrant, Rapid swelling in aqueous

medium or wicking action. Does not contain any starch or

sugar. Used in nutritional products.

L-HPC Both swelling and wicking

Gums As disintegrants because of their tendency to swell in

water

Chitin and Chitosan

Moisture sorption and water uptake was found the major

mechanism of disintegration while dissolution related to

swelling capacity

Smecta

Their layered leaves like structure consist of aluminium

and octahydral layers sandwiched between two tetrahydral

silica layers. It has a large specific area and high affinity

for water makes it good disintegrant.

Isapghula Husk Plantagoovata seeds husk has high swellability and gives

uniform and rapid disintegration.

Polacrillin Potassium

It swells up at very fast rate upon contact with water or

gastro intestinal fluid and act as an effective tablet

disintegrant

Ion Exchange Resins Resins have ability to swell in the presence of water,

showed disintegration of tablet.

Gas – Evolving disintegrants These react in contact with water to liberate carbon

dioxide that disrupts the tablet


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MATERIALS AND METHODS

Active pharmaceutical ingredient ZOLMITRIPTAN was collected as a gift sample form Intas

Pharma and other inactive ingredients were purchase locally from SD Fine Chemicals,

Hyderabad.

Formulation of ZOLMITRIPTAN oral disintegrating tablets

In this present research work oral disintegrating tablet were prepared by wet granulation

technique and direct compression method.

Formulation of oral disintegrating tablets by melt granulation technique.

Table no 03: ingredients used in formulation of Zolmitriptan tablets trial T-01 to T-05.

S. NO INGREDIENTS T-2 T-2 T-3 T-4 T-5

1 ZOLMITRIPTAN 10 10 10 10 10

2 SORBITOL 20 10 7.5 15 15

3 PEG6000 3 1.5 1.12 2.25 2.25

4 PRECIROL 0 0 0 0 0

5 AEROSIL 1 1 1 1 1

6 MANNITOL 56.3 67.8 70.63 62 59.3

7 CROSSPOVIDONE 7.5 7.5 7.5 7.5 10

8 PIPPERMINT 0.25 0.25 0.25 0.25 0.25

9 MAGNESIUM STEARATE 0.5 0.5 0.5 0.5 0.5

10 ACE SULFATE PT 1.5 1.5 1.5 1.5 1.5

TOTAL WEIGHT OF TABLET IN MG 100 100 100 100 99.8

Formulation of oral disintegrating tablets by Direct Compression technique.

Table no 04: ingredients used in formulation of Zolmitriptan tablets T-06 to T-10.

SNO DIRECTCOMPRESSION F6 F7 F8 F9 F10

1 ZOLMITRIPTAN 10 10 10 10 10

2 PRECIROL 5 7.5 10 15 7.5

3 AEROSIL 1 1 1 1 1

4 MANNITOL 74.25 71.75 69.25 64.25 69.25

5 CROSSPOVIDONE 7.5 7.5 7.5 7.5 10

6 ACE SULFATE PT 1.5 1.5 1.5 1.5 1.5

7 PIPPERMINT 0.25 0.25 0.25 0.25 0.25

8 MAGNESIUM STEARATE 0.5 0.5 0.5 0.5 0.5

TOTAL WT(mg) 100 100 100 100 100


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Preparation of oral disintegrating tablets by melt granulation method:

Melt granulation approach is a manner by which pharmaceutical powders are efficaciously

agglomerated via a soften capable binder. The advantage of this method compared to a

conventional granulation is that no water or natural solvents is needed. For accomplishing

this manner, high shear mixers are applied, wherein the product temperature is raised above

the melting factor of binder with the aid of a heating jacket or by way of the warmth of

friction generated by means of impeller blades. This technique to prepare FDT with enough

mechanical integrity, includes the usage of a hydrophilic waxy binder (Superpolystate©,

PEG-6-stearate). Superpolystate© is a waxy cloth with a melting factor of 33–37°C and a

HLB cost of nine. So it wills no longer simplest act as a binder and increase the bodily

resistance of tablets however will also help the disintegration of the tablets as it melts in the

mouth and solubilized unexpectedly leaving no residues.

Preparation of oral disintegrating tablets using direct compression method

Drug and excipients were allowed to pass through 40 # mesh one after the other and then

switch it to poly bag and mix it for three minutes.

Upload other excipients to the above aggregate al last upload the Glidant (Magnesium

Stearate) to the above combination mix it for 2min.

Compress the above lubricated combo by using 7mm spherical punches.

Preformulation Studies

A. Color, Odor, Flavor

The drug pattern changed into evaluated for its coloration and odor. The outcomes are shown

in desk.

B. Melting point willpower

Melting factor of the drug sample was determined through capillary technique by using the

use of melting factor equipment.

C. Determination of Solubility

The solubility of the Zolmitriptan become decided by using including excess quantity of drug

in the solvent and equilibrium solubility changed into determined via taking supernatant and

studying it on Perkin Elmer Lambda35, double beam spectrophotometer.


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D. Ultraviolet seen (UV-visible) spectroscopy

Determination of Calibration Curve

Preparation of stock solution

As it should be weighed a hundred mg of Zolmitriptan changed into dissolved in one hundred

ml of (1.2pH 0.1N HCl). The consequent answers have been having concentration of

thousand µg/ml (1.0 mg/ml). 10 ml of this solution become similarly diluted as much as

100.zero ml with buffer and to provide an answer of Concentrations one hundred µg/ml. This

resultant answer is used as running stock answer for similarly look at. Similarly dilutions

were organized from the identical answer.

Serial dilutions

Suitable aliquots have been pipette out from the usual inventory answer in to a chain of 10 ml

volumetric flasks. The quantity was made on top of things with buffer to get a set of solutions

having the attention variety of 2, 3, 4, 5, and 6µg/ml for Zolmitriptan. Absorbances of the

above solutions had been measured at 225 nm and a calibration curve of absorbance against

concentration was plotted and the drug follows the Beer‟s & Lambert‟s law in the

concentration range of 2-6 µg/ml. The regression equation and correlation coefficient

changed into decided.

Bulk density, Tapped density, % Compressibility index & Hausner’s ratio

Bulk Density

The bulk density was determined by moving the accurately weighed pattern of powder to the

graduated measuring cylinder. The initial volume and weight turned into cited. Ratio of

weight of the sample was calculated by the use of the following formula.

Density = Mass/quantity

Tapped Density

Weighed powder sample was transferred to a graduated cylinder and become located on the

faucet density apparatus, changed into operated for fixed variety of taps (200). The tapped

density became determined through the following method.

Density = Mass/Tapped extent

Percentage Compressibility (or) Carr’s index (%)

Based totally on the obvious bulk density and the tapped density, the proportion

Compressibility of the bulk drug became decided via the subsequent formulation.


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Carr‟s index (%) = [(Tapped Density-Bulk Density) / Tapped Density] X one hundred.

Table no 05: Compressibility limits with respective flow.

S.No %Compressibility Flow ability

1 12-May Excellent

2 16-Dec Good

3 18-21 Fair

4 23-25 Poor

5 33-38 Very poor

6 More than Discarded

Assessment of Tablets

The quantitative evaluation and evaluation of a capsules chemical, physical and

bioavailability houses are critical within the layout of tablets and to monitor product

exceptional. There are various standards that have been set within the various

pharmacopoeias regarding the first-rate of pharmaceutical drugs. Those encompass the

diameter, length, form, thickness, weight, hardness, Friability and in-vitro-dissolution

characters.

Physical characteristic

The general look of a pill, its identification and general elegance is essential for consumer

attractiveness, for manipulate of lot-to-lot uniformity and tablet-to-pill uniformity. The

fashionable appearance entails the dimension of length, shape, color, presence or absence of

odour, taste etc.

Size & shape

It is able to be dimensionally described & managed. The thickness of a pill is best variables.

Tablet thickness can be measured via micro-meter or by different tool. Tablet thickness need

to be managed within a ± 5% variation of trendy value.

Weight variant

that is an in system first-rate control take a look at to make sure that the manufacturers

manage the version in the weight of the compressed tablets, extraordinary pharmacopoeia

specify those weight variant assessments These assessments are based at the comparison of

the weight of the man or woman capsules (xi) of a pattern of drugs with an top and decrease

percent restriction of the discovered pattern common (x-mean). The USP has supplied limits

for the common weight of uncoated compressed capsules. Those are relevant whilst the tablet


767


includes 50mg or greater of the drug substance or while the latter accommodates 50% or

extra, via weight of the dosage shape.

METHOD

Twenty tablets have been weighed individually and the common weight became calculated.

The individual tablet weights are then compared to the average weight. No longer greater

than two pills have to vary in their average weight with the aid of more than percentages said

in USP. No tablet need to differ through extra than double the relevant percent.

Table no 06: Percent of limits permitted in weight variation.

Average weight of

tablet (mg)

% Difference

allowed

130 or less 10%

From 130 to 324 7.50%

> 324 5%

Content uniformity

The drug content of the oral dispersible pills become determined by standards and it meets

the necessities if the quantity of the active factor in each of 10 examined tablets lies in the

variety of 90% to 110% of the same old amount.

Ten tablets were weighed and brought into a mortar and beaten into pleasant powder. An as it

should be weighed portion of the powder equivalent to about 10mg of became transferred to

100ml volumetric flask containing 70ml of zero.1N Hcl buffer. It becomes shaken by means

of mechanical approach for 1hr then it was filtered thru Watsmann clear out paper (no.1) and

diluted to 100ml with 0.1NHcl buffer. From this resulted solution 1ml became taken, diluted

to 50ml with 0.1N HCL buffer and absorbance changed into measured against blank at 225

nm.

Friability

Friction and surprise are the forces that most usually cause capsules to chip, cap or destroy.

The friability check is closely related to pill hardness and designed to assess the capacity of

the pill to withstand abrasion in packaging, handling and delivery. It‟s also measured by way

of the use of the Roche friabilator.


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Technique

Some of drugs are weighed and located in the apparatus in which they may be uncovered to

rolling and repeated shocks as they fall 6 inches in every flip in the equipment. After 4 mins

of this remedy or a hundred revolutions, the tablets are weighed and the burden in

comparison with the preliminary weight. The loss because of abrasion is a degree of the pill

friability. The price is expressed as a percent. A maximum weight reduction of no longer

extra than 1% of the burden of the capsules being examined for the duration of the friability

test is considered commonly suited and any damaged or smashed capsules are not picked.

The percentage friability changed into decided by way of the formulation.

% friability = (W1-W2) / W1 X 100

W1 = Weight of tablets before test

W2 = Weight of tablets after test.

In-vitro Drug Release Studies

In vitro drug launch become studied the usage of USP II equipment, with 900 ml of

dissolution medium maintained at 37±1°C for 45 mnts, at 50 rpm. 0.1 N HCl (pH 1.2)

became used as a dissolution medium for the first 5mnts, accompanied by using pH 0.1N

HCL buffers for similarly 45mnts. 5ml of sample changed into withdrawn in distinctive time

intervals, and became changed by an identical volume of sparkling dissolution medium of

equal pH. Gathered samples had been analyzed spectrophotometrically at 225 nm, and

cumulative percent drug release turned into calculated. The observed turned into executed in

triplicate.

Determination of release rate kinetics

If you want to describe the DS release kinetics from individual pill formulations, the

corresponding dissolution facts were equipped in diverse kinetic dissolution fashions:

Order, first order, and Higuchi respectively.

Qt = Q0 + K0t

Where, Qt is the amount of drug launched at time t; Q0 the quantity of drug in the solution at

t = zero, (normally, Q0 = zero) and K0 the zero order launch regular.

logQt = logQα+ (K1 /2.303) t

Qα being the total amount of drug within the matrix and K1 the primary order kinetic

consistent.

Qt = KH. t ½


769


Wherein, KH is the Higuchi rate constant.

Further, to higher characterize the mechanism of drug release from matrices, dissolution

information had been analyzed the use of the equation proposed by means of Koresmeyer and

Peppas.

Q (t-l) /Qα = KK (t-l) n

Where, Qt corresponds to the quantity of drug released in time t, l is the lag time (l = 2

hours), Qα is the full quantity of drug that ought to be launched at countless time, KK a

constant comprising the structural and geometric characteristics of the tablet, and n is the

discharge exponent indicating the kind of drug release mechanism. To the determination of

the exponent n, the points in the launch curves where Q (t-l)/Qα>zero.6, had been simplest

used. If n approaches to 0.five, the release mechanism can be Fickian. If n tactics to one, the

discharge mechanism can be zero order and then again if zero.5<n<1, non-Fickian

(anomalous) transport could be received. Anomalous (non-Fickian) shipping generally refers

back to the drug launch by way of the summation of each diffusion and erosion of the

polymeric matrix. The standards employed to choose the „„fine version‟‟ changed into the one

with the very best coefficient of dedication (r2).

Stability Studies

According to ICH guide lines, the prepared in-house oral disintegrating tablets were

subjected to one month stability studies at specified temperature and humidity conditions.

1. 250C/60% RH analyzed every month for length of 1 month.

2. 300C/seventy five% RH analyzed each month for duration of 1 month.

3. 400C/75% RH analyzed each month for duration of 1 month.

RESULTS AND DISCUSSION

Results of methodology are described accordingly.

Preformulation studies of API.


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API CHARACTERIZATION

Table no 07: Physical Properties of API.

S.NO API

CHARACTERISATION RESULTS

1 Physical Appearance yellow powder

2 Melting point 135oC

3 Solubility Methanol, water

4 Bulk density 0.23GM/ML

5 Tapped Density 0.493GM/ML

6 Carr‟s index 17.32

7 Hausner‟s Ratio 1.93

The value of API compressibility index is 17.23%, 15-25%, less than 15% indicates poor

flow ability, optimum flow ability and high flow ability respectively.

Table no 08: Micrometrics Properties of final blend of trial-01 to trial T-05.

Parameter F1 F2 F3 F4 F5

Angle of repose 27055 29

o39 23

o.3

28

08 28

065

Bulk density 0.63 0.55 0.51 0.47 0.6

Tapped density 0.66 0.63 0.54 0.52 0.64

Cars index 4.76 14.54 5.88 10.6 6.66

Hausner‟s ratio 1.047 1.14 1.05 1.1 1.06

Table no 09: Micrometrics Properties of final blend of trial-06 to trial T-09.

Parameter F6 F7 F8 F9

Angle of repose 26074‟ 28

o39 21

081 24

081

Bulk density 0.57 0.46 0.42 0.61

Tapped density 0.63 0.51 0.53 0.69

%Compressibility 10.52 10.86 26.19 13.11

Hausner‟s ratio 1.1 1.1 1.15 1.13

Calibration of Zolmitriptan

Standard graph of Zolmitriptan in0.1N HCl (pH buffer).

The construction of normal activity curve of Zolmitriptan was done by mistreatment zero.1N

HCl as the medium. Zolmitriptan was found to possess the most absorbance at 225 nm. The

standard graph of Zolmitriptan in 0.1N HCl was created by creating the concentrations of

2µg/ml, 3µg/ml, 4 µg/ml, five µg/ml and six µg/ml solutions. The absorbance of solutions

was examined below UV- photometer at Associate in Nursing absorption most of 225 nm.

The quality graph of Zolmitriptan was created by taking the absorbance on coordinate axis

and concentrations on coordinate axis.


771


Table no 10: Concentrations for calibration curve.

S.

no. CONCENTRATION(µg/ml) ABSORBANCE

1 0 0

2 2 0.221

3 3 0.321

4 4 0.415

5 5 0.535

6 6 0.624

Figure no 02: Graphical representation of calibration curve.

Fourier Transformation Infra-red (FTIR) analysis

Infra-red spectroscopy analysis was performed by Fourier Transformation Infrared

Spectrophotometer Alpha Brooker FTIR (Tokyo, Japan).The instrument was calibrated by

using polystyrene film.

Figure no 03: FTIR Spectra Pure Zolmitriptan.


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Figure no 04: FTIR spectra of Zolmitriptan with Sorbital.

Figure no 05: FTIR spectra of Zolmitriptan with PEG-6000.

Figure No 07: Ftir For Zolmitriptan And Precirol.


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Figure No 08: Ftir Zolmitriptan Mannitol.

Figure No 09: Ftir Zolmitriptan All Excipients.

FTIR spectra of the data given above graphs give us the clear picture that there is no much

interaction between the pure Zolmitriptan and other inactive ingredients.

Evaluation parameters of in-house prepared tablets.

Table no 11: In-vitro evaluation parameters from T-01 to T-05


Weight variation 97 99 97 98 98

Thickness (mm) 15 15.7 23 26.5 29

Hardness (kg/cm2) 2.4 2.3 2.5 2.3 2.4

Friability(%W/W) 0.3 0.35 0.4 0.3 0.4

Content uniformity (%) 98 98.4 98.6 98.8 99


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Table no 12: In-vitro evaluation parameters from T-06 to T-10.


Weight variation 101 100 99 101 101

Thickness (mm) 34 32 41 41 42

Hardness (kg/cm2) 2.5 2.3 2.6 2.5 2.5

Friability(%W/W) 0.5 0.6 0.8 0.9 0.9

Content uniformity (%) 99.17 99 99 99.68 100

In-vitro drug release studies

Release of Zolmitriptan was observed in 0.1N HCL at regular intervals, the percent of drug

release of Zolmitriptan from in-house prepared tablets are given in below table.

Table no 13: Drug release from trial T-01 to T-05.

TIME T-1 T-2 T-3 T-4 T-5

0 0 0 0 0 0

5 5.34 10 8.12 2.98 12.12

10 40.25 15.34 14.28 39.22 28.23

15 44.37 23.45 21.82 35.68 34.23

20 68.34 49 34.23 36.72 54.23

30 87.34 23 42.45 39.62 76.93

40 90.12 34.76 54.23 55.07 88.83

50 93.28 83.25 71.23 59.36 97.34

60 95.24 98.83 88.39 98.23 99.3

Figure no 10: Graphical representation of drug release from trial T-01 to T-05.


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Table no 14: Drug release from Trial T-05 to T-10.

TIME T-6 T-7 T-8 T-09 T-10

0 0 0 0 0 0

5 10.23 10.23 6.39 5.23 8.23

10 18.36 20.34 12.84 9.26 20.43

15 23.56 32.56 35.83 16.28 35.29

20 56.04 75.35 55.38 21.74 50.12

30 75.45 88.49 64.34 35.39 65.18

40 86.45 93.24 68.83 49.38 72.85

50 92.45 95.78 78.38 64.98 84.29

60 99.56 99.34 93.45 76.28 98.38

Figure no 11: Graphical representation of drug release from trial T-06 to T-10.

OPTIMIZATION AND REPRODUCIBLE BATCH TRIAL T-10

TRIAL T-10 was optimized based on the drug release and other in-vitro evaluation

parameters and was taken for stability studies for one month accelerated conditions 60oC,

60% RH.

Table no 15: Physical characteristics of tablet after one month stability studies at

accelerated condition.

Parameter T-10

Weight variation 98

Thickness (mm) 17

Hardness (kg/cm2) 2

Friability(%W/W) 0.4

Content uniformity (%) 99


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IN-VITRO DRUG RELEASE STUDIES AFTER ONE MONTH STABILITY

STUDIES

Table no 16: Drug release studies after one month accelerated stability studies.

TIME T-10

0 0

5 6.4

10 15.39

15 24.94

20 45.93

30 67.83

40 78.33

50 86.93

60 99.73

DETERMINATION OF RELEASE RATE KINETICS

Table no 17: Data of Release rate kinetics.

ZERO ORDER FIRST ORDER HIGUCHIS PLOT KORESMEYER PEPPAS

PLOT

TIME IN

MINUTES

% DRUG UN

DISSOLVED

TIME IN

MINUTES

LOG

100-Q

SQ

TIME

% MEAN

DISSOLVED

LOG

TIME

LOG

CUMMULATIVE

% DRUG

DISSOLVED

0 0 0 0 0 0 0 0

5 93.6 5 1.97 2.24 6.4 0.7 0.81

10 84.6 10 1.93 3.16 15.39 1 1.19

15 75.1 15 1.88 3.87 24.94 1.18 1.4

20 54.1 20 1.73 4.47 45.93 1.3 1.66

30 32.2 30 1.51 5.48 67.83 1.48 1.83

40 21.7 40 1.34 6.32 78.33 1.6 1.89

50 13.1 50 1.12 7.07 86.93 1.7 1.94

60 0.3 60 -0.57 7.75 99.73 1.78 2

GRAPHICAL REPRESENTAITION OF KINEITCS OF DRUG RELEASE FROM

OPTIMIZED TRIAL T-10

ZERO ORDER

Figure no 12: Graphical representation of Zero Order Kinetics from trial T-10.


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FIRST ORDER

Figure no 13: Graphical representation of First Order Kinetics from trial T-10.

HIGUCHIS PLOT

Figure no 14: Graphical representation of HIGUCHIS Order Kinetics from trial T-10.

KORESMEYER PEPPAS PLOT

Figure no 15: Graphical representation of KORESMEYER-PEPPAS Order Kinetics

from trial T-10.

DISCUSSION

In the present work API Zolmitriptan and other inactive ingredients were taken in to

preparation based on the data of review of literature and FTIR spectra of API and other


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inactive ingredients did not show much interference between the peaks of respective

ingredients and API.

Based on the physicochemical properties of Zolmitriptan, melt granulation and direct

compression techniques methods were applied in preparation of oral disintegrating tablets.

To attain an optimized formula in using melt granulation technique for the preparation of oral

disintegrating tablets five trials were made of which trial T-5 was optimized where, all in-

vitro parameters pertaining to oral disintegrating tablets was fulfilled. Similar situation is

observed in case of direct compression technique and trial T-10 was optimized.

In case of melt granulation technique, there may be chances of losing the activity of the

Zolmitriptan as, in the process, melting and reconstituting of its physical structure will take

place.

Optimized trial T-10 was reproduced and taken for one month stability studies under

controlled temperature and humilities.

Release rate of determined based on the R2

values obtained after interpreting the drug release

data with various kinetic models and the order of release of drug follows as KORESMEYER

PEPPAS-0.989>FIRST ORDER-0.975>HIGUCHIS PLOT-0.926.

Based on the release rate kinetics data, the in-house prepared Zolmitriptan oral disintegrating

tablets follows KORESEMEYER PEPPAS MODEL for release of the drug.

CONCLUSION

The in-house prepared oral disintegrating tablets showed promising results using different

ingredients like precrol, ACE sulfate, Crosspovidone and Aerosil for all in-vitro evaluated

parameters. Base on the results acquired formulation trial T-10 was optimized for further in-

vivo studies.

ACKNOWLEDGEMENT

All the authors are thankful to Founder and promoter of SHADAN EDUCATIONAL

SOCIETY late Sri MD.VIZARAT RASOOL KHAN SAAB and chairman Mr. MD. SHA-

ALAM RASOOL KHAN for providing great infrastructure and facilities to carry out the


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present research work and Principal Dr. M SUNITHA for her continuous support till the

completion of present research work entitle.

“Formulation and In-Vitro Evaluation of Serotonin-5ht-1b and Serotonin-5ht-1d

Receptor Agonist Agent-Zolmitriptan-An Anti-Migraine Drug”

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